The Effects of Asparagus Racemosus Supplementation Plus 8 Weeks of Resistance Training on Muscular Strength and Endurance.
Previous studies have demonstrated that ayurvedic ingredients exhibit ergogenic (performance enhancing) properties, however, no previous studies have examined the ergogenic potential of Asparagus racemosus. The purpose of the present study was to examine the ergogenic efficacy of supplementation with 500 mg·d-1 of A. racemosus during bench press training. Eighteen recreationally trained men (mean ± SD; age = 20.4 ± 0.5 yrs; height = 179.7 ± 1.5 cm; weight = 84.7 ± 5.7 kg) were randomly assigned either 500 mg·d-1 of A. racemosus (n = 10) or placebo (n = 8). An overlapping sample of 10 participants were used to determine test-retest reliability. Pre- and post-training testing included bench press with one repetition maximum (1RM) and repetitions to failure at 70% of pre-training 1RM. The participants performed two sets of bench press to failure three times a week for eight weeks. Independent t-tests, Analyses of covariance (ANCOVA), and regression analyses were used to analyze the dependent variables. The results demonstrated greater mean percentage (14.3 ± 7.7% vs. 7.8 ± 4.5%; p = 0.048) and individual (80% vs. 50%) increases in 1RM, mean (17.5 ± 2.2 repetitions vs. 15.2 ± 2.2 repetitions; p = 0.044) and individual (80% vs. 38%) increases in repetitions to failure, and a greater rate of increase in training loads for the Asparagus racemosus group than the placebo group. In conjunction with bench press training, supplementation with A. racemosus provided ergogenic benefits compared to placebo.


Visual outcomes of eyes implanted with a toric multifocal intraocular lens.
To investigate the predictability, efficacy, and safety of a ReSTOR multifocal intraocular lens (IOL) (Alcon Laboratories, Inc., Fort Worth, TX). This retrospective, noncomparative case study included 70 eyes of 44 patients implanted with a ReSTOR toric multifocal IOL (Alcon Laboratories, Inc., Fort Worth, TX). Patients were examined preoperatively and approximately 3 months postoperatively. Uncorrected and distance-corrected distance and near visual acuities were measured. Refractive and topographic astigmatism were recorded. Improvement, number of lines gained and lost, and correlation of attempted and achieved astigmatic correction values were also investigated as measurements of efficacy, safety, and predictability. Mean follow-up time was 2.3 ± 1.2 months. Postoperative values of uncorrected distance and near visual acuity were 0.02 ± 0.05 logMAR (20/21 ± 20/22 Snellen) and 0.01 ± 0.04 logMAR (20/20 ± 20/22 Snellen), respectively. Statistical analyses revealed a significant improvement when comparing preoperative and postoperative values of manifest refraction spherical equivalent (P < .0001), uncorrected distance visual acuity (P < .0001), and astigmatism (P < .0001); 95.7% of eyes were 20/25 or better and 100% of eyes were 20/30 or better. At the last follow-up visit, none of the examined eyes had lost any lines. One hundred percent of the eyes remained unchanged or improved after surgery. Mean postoperative manifest refraction spherical equivalent was -0.06 ± 0.27 at the last follow-up visit. The residual manifest astigmatism was 0.22 ± 0.21. There was a highly significant correlation between preoperative attempted topographic astigmatism and postoperative achieved refractive astigmatism. The study provides clinical evidence that the new toric multifocal IOL seems to be predictable, safe, and effective, providing satisfactory visual acuity for far and near and correcting astigmatism.


Observation of sonified movements engages a basal ganglia frontocortical network.
Producing sounds by a musical instrument can lead to audiomotor coupling, i.e. the joint activation of the auditory and motor system, even when only one modality is probed. The sonification of otherwise mute movements by sounds based on kinematic parameters of the movement has been shown to improve motor performance and perception of movements. Here we demonstrate in a group of healthy young non-athletes that congruently (sounds match visual movement kinematics) vs. incongruently (no match) sonified breaststroke movements of a human avatar lead to better perceptual judgement of small differences in movement velocity. Moreover, functional magnetic resonance imaging revealed enhanced activity in superior and medial posterior temporal regions including the superior temporal sulcus, known as an important multisensory integration site, as well as the insula bilaterally and the precentral gyrus on the right side. Functional connectivity analysis revealed pronounced connectivity of the STS with the basal ganglia and thalamus as well as frontal motor regions for the congruent stimuli. This was not seen to the same extent for the incongruent stimuli. We conclude that sonification of movements amplifies the activity of the human action observation system including subcortical structures of the motor loop. Sonification may thus be an important method to enhance training and therapy effects in sports science and neurological rehabilitation.


Bacterial infection remodels the DNA methylation landscape of human dendritic cells.
DNA methylation is an epigenetic mark thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells (DCs) with a live pathogenic bacteria is associated with rapid and active demethylation at thousands of loci, independent of cell division. We performed an integrated analysis of data on genome-wide DNA methylation, histone mark patterns, chromatin accessibility, and gene expression, before and after infection. We found that infection-induced demethylation rarely occurs at promoter regions and instead localizes to distal enhancer elements, including those that regulate the activation of key immune transcription factors. Active demethylation is associated with extensive epigenetic remodeling, including the gain of histone activation marks and increased chromatin accessibility, and is strongly predictive of changes in the expression levels of nearby genes. Collectively, our observations show that active, rapid changes in DNA methylation in enhancers play a previously unappreciated role in regulating the transcriptional response to infection, even in nonproliferating cells.


Immune phenotype of peripheral blood cells and skin squamous cell carcinoma in organ transplant recipients.
Evaluation of: Carroll RP, Segundo DS, Hollowood K et al. Immune phenotype predicts risk for posttransplantation squamous cell carcinoma. J. Am. Soc. Nephrol. 21, 713-722 (2010). Squamous cell carcinoma (SCC) of the skin is a common tumor in Caucasians, occurring on sun-damaged skin. The carcinogenesis of SCC is multifactorial and the most important risk factor is UV radiation. Interestingly, SCC is the most frequent malignancy following organ transplantation, with a 60-100-fold increased risk compared with the general population. Carroll et al. recently identified more than 35 FOXP3+ cells per microl and less than 100 natural killer cells per microl in peripheral blood and previous SCC as risk factors for SCC in renal transplant recipients. The ratio of CD8/FOXP3 cells was significantly lower in the microenvironment of SCC from kidney transplant recipients compared with immunocompetent patients. These findings provide hitherto unknown details about the potential influence of immunomodulation by drugs on the development of SCC in kidney transplant recipients. While this study population may not relate to all kidney transplant recipients, particularly those on other immunosuppressive regimens, Carroll et al. provide us with a tool to aid recognition of patients at a higher risk for SCC. Further studies will help to translate these findings into potentially useful tools for the dermatological management of kidney transplant recipients.


The positive effects of different platelet-rich plasma methods on human muscle, bone, and tendon cells.
Clinical application of platelet-rich plasma (PRP) in the realm of orthopaedic sports medicine has yielded variable results. Differences in separation methods and variability of the individual may contribute to these variable results. To compare the effects of different PRP separation methods on human bone, muscle, and tendon cells in an in vitro model. Controlled laboratory study. Blood collected from 8 participants (mean ± SD age 31.6 ± 10.9 years) was used to obtain PRP preparations. Three different PRP separation methods were used: a single-spin process yielding a lower platelet concentration (PRP(LP)), a single-spin process yielding high platelet and white blood cell concentrations (PRP(HP)), and a double-spin that produces a higher platelet concentration and lower white blood cell concentration (PRP(DS)). Human bone, muscle, and tendon cells obtained from discarded tissue samples during shoulder surgery were placed into culture and treated with the 3 PRP preparations, control media (2% fetal bovine serum [FBS] and 10% FBS), and native blood. Radioactive thymidine assays were obtained to examine cell proliferation, and testing with enzyme-linked immunosorbent assay was used to determine growth factor concentrations. Addition of PRP(LP) to osteocytes, myocytes, and tenocytes significantly increased cell proliferation (P ≤ .05) compared with the controls. Adding PRP(DS) to osteoblasts and tenocytes increased cell proliferation significantly (P ≤ .05), but no significance was shown for its addition to myocytes. The addition of PRP(HP) significantly increased cell proliferation compared with the controls only when added to tenocytes (P ≤ .05). Osteoblasts: Proliferation was significantly increased by addition of PRP(LP) compared with all controls (2% FBS, 10% FBS, native blood) (P ≤ .05). Addition of PRP(DS) led to significantly increased proliferation compared with all controls, native blood, and PRP(HP) (P ≤ .05). Proliferation was significantly less when PRP(HP) was added compared with PRP(DS) (P ≤ .05). Myocytes: Proliferation was significantly increased by addition of PRP(LP) compared with native blood (P ≤ .05). Adding PRP(HP) or PRP(DS) to myocytes showed no significant increase in proliferation compared with the controls or the other separations. Tenocytes: Proliferation was significantly increased by addition of PRP(LP) compared with all controls (2% FBS, 10% FBS, native blood) (P ≤ .05). Addition of PRP(DS) showed a significant increase compared with the controls and native blood. For tenocytes, there was a significant increase (P ≤ .05) seen when PRP(HP) was added compared with the controls and native blood but not compared with the other separations. The primary findings of this study suggest the application of different PRP separations may result in a potential beneficial effect on the clinically relevant target cells in vitro. However, it is unclear which platelet concentration or PRP preparation may be optimal for the treatment of various cell types. In addition, a "more is better" theory for the use of higher platelet concentrations cannot be supported. This study was not intended to prove efficacy but to provide a platform for future research to be built upon. The utilization of different PRP separations may result in a potentially beneficial effect on the clinically relevant target cells in vitro, but it is unclear which platelet concentration or PRP preparation may be optimal for the treatment of various cell types.


IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells.
The role of IGF binding protein 2 (IGFBP2) in cell growth is intriguing and largely undefined. Previously we identified IGFBP2 as an extrinsic factor that supports ex vivo expansion of hematopoietic stem cells (HSCs). Here we showed that IGFBP2-null mice have fewer HSCs than wild-type mice. While IGFBP2 has little cell-autonomous effect on HSC function, we found decreased in vivo repopulation of HSCs in primary and secondary transplanted IGFBP2-null recipients. Importantly, bone marrow stromal cells that are deficient for IGFBP2 have significantly decreased ability to support the expansion of repopulating HSCs. To investigate the mechanism by which IGFBP2 supports HSC activity, we demonstrated that HSCs in IGFBP2-null mice had decreased survival and cycling, down-regulated expression of antiapoptotic factor Bcl-2, and up-regulated expression of cell cycle inhibitors p21, p16, p19, p57, and PTEN. Moreover, we found that the C-terminus, but not the RGD domain, of extrinsic IGFBP2 was essential for support of HSC activity. Defective signaling of the IGF type I receptor did not rescue the decreased repopulation of HSCs in IGFBP2-null recipients, suggesting that the environmental effect of IGFBP2 on HSCs is independent of IGF-IR mediated signaling. Therefore, as an environmental factor, IGFBP2 supports the survival and cycling of HSCs.


[Titrated oral solution of misoprostol for labour induction: a pilot study].
To test effectiveness and safety of the oral administration of a new misoprostol formulation in titrated doses for the induction of delivery of a live fetus at term. An open pilot multicenter, non-randomized clinical trial was conducted from July to December 2008. A total of 30 patients with indications for induction of labor were included. The patients had a live fetus, Bishop score <6, vertex presentation, fetal weight <4,000g estimated by ultrasonography and amniotic fluid index >5. Exclusion criteria were previous uterine scar, non-reassuring fetal heart rate tracing, multiple pregnancy, fetal growth restriction, genital hemorrhage and presence of genital tumors, ulcerations or malformations. An initial dose of 20 µg/hour of the oral misoprostol solution was used in the first 6 hours, and was increased progressively to 20 µg/hour every 6 hours if labor did not start, up to a maximum dose of 80 µg/h in the first 24 hours, maintained for additional 24 hours if necessary. Labor was satisfactorily induced in 96.7% of patients. The interval between the first dose and the beginning of uterine contractions was 3.8 ± 1.8 hours. The interval between the initial dose and delivery varied from 6 to 24 hours. The frequency of vaginal delivery was 80% (24 cases). Most of the patients (60%; n=18) initiated labor with a dose of 20 mg/hour. Tachysystole occurred in 13.3% of women and meconium-stained fluid was detected in 20% of cases. There were two cases of Apgar scores < 7 in the first minute and no Apgar score < 7 in the fifth minute. The oral solution of misoprostol was effective and safe for the induction of labor. However, further randomized controlled trials are needed to compare this new formulation with misoprostol administered by the vaginal route.


Influence of Host Resistance and Insecticide Seed Treatments on Curly Top in Sugar Beets.
Curly top on sugar beets (Beta vulgaris) caused by Beet severe curly top virus or closely related species is a considerable problem in arid growing regions of the western United States. Two insecticide seed treatments, Poncho Beta (60 g a.i. clothianidin + 8 g a.i. beta-cyfluthrin/100,000 seed) and Gaucho (45 g a.i. imidacloprid/100,000 seed), and four sugar beet hybrids varying in curly top resistance were evaluated for their influence on the control of curly top in comparison with untreated checks. Plots were established at two locations in southern Idaho in 2005 and evaluated for curly top. Moderate to severe curly top due to natural inoculum and leafhopper infestations occurred at both locations. Untreated, the four hybrids performed as expected with the fewest curly top symptoms on PM21 and the most on Monohikari. Both insecticide treatments lowered curly top ratings compared with the untreated check, but Poncho Beta reduced symptoms more than Gaucho as the season progressed. Poncho Beta led to increased yield and estimated recoverable sugar across all hybrids at harvest, particularly on the more susceptible hybrids. When considering the yield parameters for only the most resistant hybrids individually, Poncho Beta did not always outperform Gaucho. Poncho Beta provided a level of control that would justify its application as a supplement to host resistance under Idaho conditions.


Hospital prices and market structure in the hospital and insurance industries.
There has been substantial consolidation among health insurers and hospitals, recently, raising questions about the effects of this consolidation on the exercise of market power. We analyze the relationship between insurer and hospital market concentration and the prices of hospital services. We use a national US dataset containing transaction prices for health care services for over 11 million privately insured Americans. Using three years of panel data, we estimate how insurer and hospital market concentration are related to hospital prices, while controlling for unobserved market effects. We find that increases in insurance market concentration are significantly associated with decreases in hospital prices, whereas increases in hospital concentration are non-significantly associated with increases in prices. A hypothetical merger between two of five equally sized insurers is estimated to decrease hospital prices by 6.7%.


Redo aortic valve surgery with endovascular control of the internal thoracic artery graft.
Redo aortic valve surgery (AVS) in patients with patent pedicled internal thoracic artery (ITA) grafts remains a challenging procedure because of the possibility of injury to the grafts and difficulties in optimal myocardial protection. This procedure is associated with a significant mortality and morbidity. Different approaches to myocardial protection and ITA graft dissection and control have been described. An intraoperative technique is proposed that provides endovascular control of the ITA graft, using an angioplasty balloon positioned during cross-clamping. Ten consecutive patients with previous coronary artery bypass grafting (CABG) and a patent pedicled ITA who underwent AVS were studied. The ITA grafts were occluded by using an angioplasty balloon during cross-clamping, but were not dissected and controlled. Endovascular control of the ITA graft was feasible in all cases, without complication. Two intraoperative complications (both graft injuries) were observed; one injury of an ITA graft, and one injury of a radial artery graft. There was no postoperative mortality. One myocardial infarct was related to the injury of a radial graft. The clamped ITA grafts were studied at two months after the procedure in five patients, and showed all grafts to be patent. At a mean follow up of 13 months, all patients were alive without any coronary events. The endovascular control of a patent ITA graft during redo AVS is a safe and simple technique that reduces the risk of ITA graft injury and also improves myocardial protection.


Structure, function and evolution of the Archaeal class I fructose-1,6-bisphosphate aldolase.
FBPA (fructose-1,6-bisphosphate aldolase) catalyses the reversible aldol condensation of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate to form fructose 1,6-bisphosphate. Two classes of FBPA, which rely on different reaction mechanisms, have so far been discovered, class I mainly found in Eucarya and class II mainly in Bacteria. Only recently were genes encoding proteins with FBPA activity identified in Archaea. Archaeal FBPAs do not share any significant overall sequence identity with members of the traditional classes of FBPAs, raising the interesting question of whether they have evolved independently by convergent evolution or diverged from a common ancestor. Biochemical characterization of FBPAs of the two hyperthermophilic Archaea Thermoproteus tenax and Pyrococcus furiosus showed that the enzymes use a Schiff-base mechanism and thus belong to the class I aldolases. The crystal structure of the archaeal FBPA from T. tenax revealed that the protein fold, as for the classical FBPA I and II, is that of a parallel (betaalpha)(8) barrel. A substrate-bound crystal structure allowed detailed active-site comparisons which showed the conservation of six important catalytic and substrate-binding residues between the archaeal and the classical FBPA I. This observation provides further evidence that the two sequence families of proteins share a common evolutionary origin. Furthermore, structure and sequence analysis indicate that the class I FBPA shares a common evolutionary origin with several other enzyme superfamilies of the (betaalpha)(8) barrel fold.


Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist.
Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD). Using aged ( approximately 16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-beta (Abeta) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-L-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor gamma agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Abeta levels or Abeta plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function.


Number of People Blind or Visually Impaired by Cataract Worldwide and in World Regions, 1990 to 2010.
To estimate prevalence and number of people visually impaired or blind due to cataract. Based on the Global Burden of Diseases Study 2010 and ongoing literature research, we examined how many people were affected by moderate to severe vision impairment (MSVI; presenting visual acuity <6/18, ≥3/60) and blindness (presenting visual acuity <3/60) due to cataract. In 2010, of overall 32.4 million blind and 191 million vision impaired, 10.8 million people were blind and 35.1 million were visually impaired due to cataract. Cataract caused worldwide 33.4% of all blindness in 2010, and 18.4% of all MSVI. These figures were lower in the high-income regions (<15%) and higher (>40%) in South and Southeast Asia and Oceania. From 1990 to 2010, the number of blind or visually impaired due to cataract decreased by 11.4% and by 20.2%, respectively; the age-standardized global prevalence of cataract-related blindness and MSVI reduced by 46% and 50%, respectively, and the worldwide crude prevalence of cataract-related blindness and MSVI reduced by 32% and 39%, respectively. The percentage of global blindness and MSVI caused by cataract decreased from 38.6% to 33.4%, and from 25.6% to 18.4%, respectively. This decrease took place in almost all world regions, except East Sub-Saharan Africa. In 2010, one in three blind people was blind due to cataract, and one of six visually impaired people was visually impaired due to cataract. Despite major improvements in terms of reduction of prevalence, cataract remains a major public health problem.


Towards a Fuzzy Expert System on Toxicological Data Quality Assessment.
Quality assessment (QA) requires high levels of domain-specific experience and knowledge. QA tasks for toxicological data are usually performed by human experts manually, although a number of quality evaluation schemes have been proposed in the literature. For instance, the most widely utilised Klimisch scheme1 defines four data quality categories in order to tag data instances with respect to their qualities; ToxRTool2 is an extension of the Klimisch approach aiming to increase the transparency and harmonisation of the approach. Note that the processes of QA in many other areas have been automatised by employing expert systems. Briefly, an expert system is a computer program that uses a knowledge base built upon human expertise, and an inference engine that mimics the reasoning processes of human experts to infer new statements from incoming data. In particular, expert systems have been extended to deal with the uncertainty of information by representing uncertain information (such as linguistic terms) as fuzzy sets under the framework of fuzzy set theory and performing inferences upon fuzzy sets according to fuzzy arithmetic. This paper presents an experimental fuzzy expert system for toxicological data QA which is developed on the basis of the Klimisch approach and the ToxRTool in an effort to illustrate the power of expert systems to toxicologists, and to examine if fuzzy expert systems are a viable solution for QA of toxicological data. Such direction still faces great difficulties due to the well-known common challenge of toxicological data QA that "five toxicologists may have six opinions". In the meantime, this challenge may offer an opportunity for expert systems because the construction and refinement of the knowledge base could be a converging process of different opinions which is of significant importance for regulatory policy making under the regulation of REACH, though a consensus may never be reached. Also, in order to facilitate the implementation of Weight of Evidence approaches and in silico modelling proposed by REACH, there is a higher appeal of numerical quality values than nominal (categorical) ones, where the proposed fuzzy expert system could help. Most importantly, the deriving processes of quality values generated in this way are fully transparent, and thus comprehensible, for final users, which is another vital point for policy making specified in REACH. Case studies have been conducted and this report not only shows the promise of the approach, but also demonstrates the difficulties of the approach and thus indicates areas for future development.


Postural Control Entropy Is Increased When Adopting an External Focus of Attention.
Falls in older adults are a public health challenge due to their influence on well-being and health-care costs. One way to address this challenge is to discover new methods to enhance postural control in older adults so they are better prepared to maintain an upright stance. Older and younger adults (N = 32) performed a static balance task on a force plate with no instructions, internal focus instructions, or external focus instructions. Center of pressure displacement time series were analyzed using sample entropy and standard deviation. Only the external focus condition significantly increased postural control entropy, which was observed across both age groups. This study showed that an external focus of attention can be used to increase postural control entropy within a single session of testing.


Pharmacological target therapy of neuropathic pain and patient-reported outcomes in patients with chronic low back pain in Korea: Results from the NLBP Outcomes Research.
A number of studies have demonstrated an association of neuropathic pain and chronic low back pain (CLBP), but the outcome difference in each medical management is poorly understood. This study is aimed to investigate treatment patterns of neuropathic pain in CLBP patients and to explore patient-reported outcomes (PROs) including quality of life (QoL) and functional disability by treatment patterns.Data were extracted from the neuropathic low back pain (NLBP) outcomes research. It was a multicenter and cross-sectional study in which 1200 patients were enrolled at 27 general hospitals, from 2014 to 2015. Of total, 478 patients classified as neuropathic pain were used for this subgroup analysis. The patients were divided into 2 groups according to treatment patterns (with vs. without the targeted therapy [TT] of neuropathic pain). Demographic and clinical features were collected by chart reviews and PROs were measured by patient's survey. QoL was assessed by EuroQoL 5-dimension (EQ-5D) questionnaire. Functional disability was measured by the Quebec Back Pain Disability Scale (QBPDS). Multiple linear regression analyses were conducted to compare the PROs between TT group and non-targeted therapy (nTT) group.Among the NLBP patients (mean age 63years, female 62%), EQ-5D index, EuroQoL-Visual Analog Scale (EQ-VAS), and QBPDS Scores (mean ± standard deviation) were 0.40 ± 0.28, 54.98 ± 19.98, and 46.03 ± 21.24, respectively. Only 142 (29.7%) patients had pharmacological TT of neuropathic pain. Univariate analyses revealed no significant mean differences between TT group and nTT group in the EQ-5D index (0.41 ± 0.27 and 0.39 ± 0.28), EQ-VAS (56.43 ± 18.17 and 54.37 ± 20.69), and QBPDS (45.31 ± 21.32 and 46.31 ± 21.24). After adjustment with covariates, TT group had higher scores of EQ-5D index (β = 0.07; P < 0.01) and EQ-VAS (β = 4.59; P < 0.05) than the nTT group. The TT group's QBPDS score was lower than the nTT group, although its statistical significance still has not been reached (β = -4.13; P = 0.07).We found that considerable proportion of the NLBP patients remains untreated or undertreated. Although TT group had significantly better QoL than nTT group, only 29.7% of NLBP patients had pharmacological TT. Therefore, clinicians should consider using TT for better QoL of neuropathic pain patients.


Mitochondrial DNA haplogroup R predicts survival advantage in severe sepsis in the Han population.
To determine whether the main mitochondrial DNA (mtDNA) haplogroups of the Han people have an impact on long-term clinical outcome. We prospectively studied 181 individuals who were sequentially admitted to the intensive care unit. Demographic and clinical data were recorded along with clinical outcome over 180 days. Follow-up was completed for all study participants. We then determined the mtDNA haplogroups of the patients and 570 healthy, age-matched Han people from Zhejiang province, Southeast China, by analyzing sequences of hypervariable mtDNA segments and testing diagnostic polymorphisms in the mtDNA coding region with DNA probes. The frequency of the main subhaplogroups of the Han population in the study cohort did not differ significantly from the control group. mtDNA haplogroup R, one of the three main mtDNA haplogroups of the Han people, was a strong independent predictor for the outcome of severe sepsis, conferring a 4.68-fold (95% CI 1.903-10.844, P = 0.001) increased chance of survival at 180 days compared with those without the haplogroup R. In the Han population, mtDNA haplogroup R was a strong independent predictor for the outcome of severe sepsis, conferring an increased chance of long-term survival compared with individuals without the R haplogroup.


Cloning of a cDNA encoding bovine erythropoietin and analysis of its transcription in selected tissues.
A bovine cDNA encoding erythropoietin (Epo) was isolated by polymerase chain reaction (PCR) amplification and screening of a bovine kidney cDNA library. The sequenced cDNA has a length of 1312 bp and an open reading frame that encodes a predicted 192-amino-acid (aa) protein, including a putative signal sequence of 25 aa. A mature protein of 167 aa (18.4 kDa) results upon cleavage of the putative signal peptide. The deduced bovine mature Epo peptide exhibits 96, 88, 83, 82 and 79% sequence identity to that of sheep, swine, human, monkey and rat, respectively. The expression of the bovine Epo gene in tissues from a severely anemic calf, bovine fetus and a healthy steer was analysed by a competitive RT-PCR method. In kidneys of the severely anemic calf, Epo mRNA levels increased 60-fold relative to that from the kidneys of the healthy steer. Epo mRNA levels were threefold higher in the liver of the bovine fetus than that in its kidneys. Low levels of Epo transcripts were detected in RNA from spleen of the severely anemic calf and the bovine fetus. No Epo transcripts were detectable in spleen from the healthy steer.


Traditional ecological knowledge trends in the transition to a market economy: empirical study in the Doñana natural areas.
Researchers and conservation managers largely agree on the relevance of traditional ecological knowledge for natural resource management in indigenous communities, but its prevalence and role as societies modernize are contested. We analyzed the transmission of traditional knowledge among rural local people in communities linked to protected areas in Doñana, southwestern Spain. We studied changes in knowledge related to local practices in agriculture and livestock farming among 198 informants from three generations that cover the period in which the area transited from an economy strongly dependent on local ecosystem services to a market economy with intensified production systems. Our results suggest an abrupt loss of traditional agricultural knowledge related to rapid transformations and intensification of agricultural systems, but maintenance of knowledge of traditional livestock farming, an activity allowed in the protected areas that maintains strong links with local cultural identity. Our results demonstrate the potential of protected areas in protecting remaining bodies of traditional ecological knowledge in developed country settings. Nevertheless, we note that strict protection in cultural-landscape-dominated areas can disrupt transmission of traditional knowledge if local resource users and related practices are excluded from ecosystem management.


Mesenchymal stem cells, autoimmunity and rheumatoid arthritis.
The vast majority of literature pertaining to mesenchymal stem cells (MSC) immunomodulation has focussed on bone marrow-derived MSC that are systemically infused to alleviate inflammatory conditions. Rheumatoid arthritis (RA) is the commonest autoimmune joint disease that has witnessed significant therapeutic advances in the past decade, but remains stubbornly difficult to treat in a subset of cases. Pre-clinical research has demonstrated that bone marrow, adipose, synovial and umbilical cord-derived MSC all suppress the functions of different immune cells thus raising the possibility of new therapies for autoimmune diseases including RA. Indeed, preliminary evidence for MSC efficacy has been reported in some cases of RA and systemic lupus erythromatosis. The potential use of bone marrow-MSC (BM-MSC) for RA therapy is emerging but the use of synovial MSC (S-MSC) to suppress the exaggerated immune response within the inflamed joints remains rudimentary. Synovial fibroblasts that are likely derived from S-MSCs, also give rise to a cell-cultured progeny termed fibroblast-like synoviocytes (FLS), which are key players in the perpetuation of joint inflammation and destruction. A better understanding of the link between these cells and their biology could be a key to developing novel MSC-based strategies for therapy. The review briefly focuses on BM-MSC and gives particular attention to joint niche synovial MSC and FLS with respect to immunoregulatory potential therapy roles.


pH-Sensitive PEGylated liposomes functionalized with a fibronectin-mimetic peptide show enhanced intracellular delivery to colon cancer cell.
pH-sensitive liposomes undergo rapid destabilization under mildly acidic conditions such as those found in endocytotic vesicles. Though this makes them promising drug carriers, their application is limited due to their rapid clearance from circulation by the reticulo-endothelial system. Researchers have therefore used pH-sensitive liposomes that are sterically stabilized by polyethylene glycol (PEG) molecules (stealth liposomes) on the liposome surface. The goal of this study is to bring bio-functionality to pH-sensitive PEGylated liposomes in order to facilitate their potential use as a targeted drug delivery agent. To improve the selectivity of these nanoparticles, we included a targeting moiety, PR_b which specifically recognizes and binds to integrin α(5)β(1) expressing cells. PR_b (KSSPHSRN(SG)(5)RGDSP) is a novel fibronectin-mimetic peptide sequence that mimics the cell adhesion domain of fibronectin. Integrin α(5)β(1) is expressed on several types of cancer cells, including colon cancer, and plays an important role in tumor growth and metastasis. We have thoroughly studied the release of calcein from pH-sensitive PEGylated liposomes by varying the lipid composition of the liposomes in the absence and presence of the targeting peptide, PR_b, and accounting for the first time for the effect of both pH and time (photo-bleaching effect) on the fluorescence signal of calcein. We have demonstrated that we can design PR_b-targeted pH-sensitive PEGylated liposomes, which can undergo destabilization under mildly acidic conditions and have shown that incorporating the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b-targeted pH-sensitive PEGylated liposomes bind to CT26.WT colon carcinoma cells that express integrin α(5)β(1), undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. Our studies demonstrate that PR_b-functionalized pH-sensitive targeted delivery systems have the potential to deliver a payload directly to cancer cells in an efficient and specific manner.


Silver nanoparticle effects on stream periphyton during short-term exposures.
Silver nanoparticles (AgNP) are increasingly used as antimicrobials in consumer products. Subsequently released into aquatic environments, they are likely to come in contact with microbial communities like periphyton, which plays a key role as a primary producer in stream ecosystems. At present, however, very little is known about the effects of nanoparticles on processes mediated by periphyton communities. We assessed the effects of citrate-coated silver nanoparticles and silver ions (dosed as AgNO3) on five functional end points reflecting community and ecosystem-level processes in periphyton: photosynthetic yield, respiration potential, and the activity of three extracellular enzymes. After 2 h of exposure in experimental microcosms, AgNP and AgNO3 inhibited respiration and photosynthesis of periphyton and the activities of two of the three extracellular enzymes. Addition of a chelating ligand that complexes free silver ions indicated that, in most cases, toxicity of AgNP suspensions was caused by Ag(I) dissolved from the particles. However, these suspensions inhibited one of the extracellular enzymes (leucine aminopeptidase), pointing to a specific nanoparticle effect independent of the dissolved Ag(I). Thus, our results show that both silver nanoparticles and silver ions have potential to disrupt basic metabolic functions and enzymatic resource acquisition of stream periphyton.


Over-the-barrier transition state analogues and crystal structure with Mycobacterium tuberculosis purine nucleoside phosphorylase.
Stable chemical analogues of enzymatic transition states are imperfect mimics since they lack the partial bond character of the transition state. We synthesized structural variants of the Immucillins as transition state analogues for purine nucleoside phosphorylase and characterized them with the enzyme from Mycobacterium tuberculosis (MtPNP). PNPs form transition states with ribooxacarbenium ion character and catalyze nucleophilic displacement reactions by migration of the cationic ribooxacarbenium carbon between the enzymatically immobilized purine and phosphate nucleophiles. As bond-breaking progresses, carbocation character builds on the ribosyl group, the distance between the purine and the carbocation increases, and the distance between carbocation and phosphate anion decreases. Transition state analogues were produced with carbocation character and increased distance between the ribooxacarbenium ion and the purine mimics by incorporating a methylene bridge between these groups. Immucillin-H (ImmH), DADMe-ImmH, and DADMe-ImmG mimic the transition state of MtPNP and are slow-onset, tight-binding inhibitors of MtPNP with equilibrium dissociation constants of 650, 42, and 24 pM. Crystal structures of MtPNP complexes with ImmH and DADMe-ImmH reveal an ion-pair between the inhibitor cation and the nucleophilic phosphoryl anion. The stronger ion-pair (2.7 A) is found with DADMe-ImmH. The position of bound ImmH resembles the substrate side of the transition state barrier, and DADMe-ImmH more closely resembles the product side of the barrier. The ability to probe both substrate and product sides of the transition state barrier provides expanded opportunities to explore transition state analogue design in N-ribosyltransferases. This approach has resulted in the highest affinity transition state analogues known for MtPNP.


Resting-state functional connectivity reflects structural connectivity in the default mode network.
Resting-state functional connectivity magnetic resonance imaging (fcMRI) studies constitute a growing proportion of functional brain imaging publications. This approach detects temporal correlations in spontaneous blood oxygen level-dependent (BOLD) signal oscillations while subjects rest quietly in the scanner. Although distinct resting-state networks related to vision, language, executive processing, and other sensory and cognitive domains have been identified, considerable skepticism remains as to whether resting-state functional connectivity maps reflect neural connectivity or simply track BOLD signal correlations driven by nonneural artifact. Here we combine diffusion tensor imaging (DTI) tractography with resting-state fcMRI to test the hypothesis that resting-state functional connectivity reflects structural connectivity. These 2 modalities were used to investigate connectivity within the default mode network, a set of brain regions--including medial prefrontal cortex (MPFC), medial temporal lobes (MTLs), and posterior cingulate cortex (PCC)/retropslenial cortex (RSC)--implicated in episodic memory processing. Using seed regions from the functional connectivity maps, the DTI analysis revealed robust structural connections between the MTLs and the retrosplenial cortex whereas tracts from the MPFC contacted the PCC (just rostral to the RSC). The results demonstrate that resting-state functional connectivity reflects structural connectivity and that combining modalities can enrich our understanding of these canonical brain networks.


Soil-transmitted helminth infection in pregnancy and long-term child neurocognitive and behavioral development: A prospective mother-child cohort in Benin.
An estimated 30% of women in Sub-Saharan Africa suffer from soil-transmitted helminth infection during pregnancy (SHIP), which has been shown to increase risk of pre-term birth, low birth weight, and maternal anemia. A previous study in Benin found that SHIP was associated with impaired cognitive and gross motor development scores in 635 one-year-old children. The objective of the present study was to follow children prospectively to investigate whether the association between SHIP and child neurocognitive and behavioral development persisted at age six. Our prospective child cohort included 487 live-born singletons of pregnant women enrolled in the Malaria in Pregnancy Preventive Alternative Drugs clinical trial in Allada, Benin. SHIP was assessed at three antenatal visits (ANVs) through collection and testing of stool samples. Neurocognitive and behavioral development was assessed in six-year-old children by trained investigators using the Kaufman Assessment Battery for Children 2nd edition and the parent-reported Strengths and Difficulties Questionnaire (SDQ). Multiple linear regression models generated coefficients and 95% confidence intervals and potential mediating factors were tested. Prevalence of SHIP was 13% at the 1st ANV, 9% at the 2nd ANV, and 1% at delivery. SHIP was not associated with low neurocognitive scores in children at six years. Higher SDQ internalizing scores, indicating increased emotional impairments in children, were associated with helminth infection at the 2nd ANV/delivery 1.07 (95% CI 0.15, 2.00) and at least once during pregnancy 0.79 (95% CI 0.12, 1.46) in adjusted models. Mediation analysis did not reveal significant indirect effects of several mediators on this association. Our study shows that while SHIP is not associated with impaired long-term neurocognitive development, infections may have significant negative impacts on emotional development in six-year-old children. SHIP remains a critical public health issue, and adequate prevention and treatment protocols should be enforced in low- and middle-income countries.


The effect of electrolyte composition on the electroreduction of CO2 to CO on Ag based gas diffusion electrodes.
The electroreduction of CO2 to C1-C2 chemicals can be a potential strategy for utilizing CO2 as a carbon feedstock. In this work, we investigate the effect of electrolytes on the electroreduction of CO2 to CO on Ag based gas diffusion electrodes. Electrolyte concentration was found to play a major role in the process for the electrolytes (KOH, KCl, and KHCO3) studied here. Several fold improvements in partial current densities of CO (jCO) were observed on moving from 0.5 M to 3.0 M electrolyte solution independent of the nature of the anion. jCO values as high as 440 mA cm(-2) with an energy efficiency (EE) of ≈ 42% and 230 mA cm(-2) with EE ≈ 54% were observed when using 3.0 M KOH. Electrochemical impedance spectroscopy showed that both the charge transfer resistance (Rct) and the cell resistance (Rcell) decreased on moving from a 0.5 M to a 3.0 M KOH electrolyte. Anions were found to play an important role with respect to reducing the onset potential of CO in the order OH(-) (-0.13 V vs. RHE) < HCO3(-) (-0.46 V vs. RHE) < Cl(-) (-0.60 V vs. RHE). A decrease in Rct upon increasing electrolyte concentration and the effect of anions on the cathode can be explained by an interplay of different interactions in the electrical double layer that can either stabilize or destabilize the rate limiting CO2˙(-) radical. EMIM based ionic liquids and 1 : 2 choline Cl urea based deep eutectic solvents (DESs) have been used for CO2 capture but exhibit low conductivity. Here, we investigate if the addition of KCl to such solutions can improve conductivity and hence jCO. Electrolytes containing KCl in combination with EMIM Cl, choline Cl, or DESs showed a two to three fold improvement in jCO in comparison to those without KCl. Using such mixtures can be a strategy for integrating the process of CO2 capture with CO2 conversion.


Crystal structure of the human p58 killer cell inhibitory receptor (KIR2DL3) specific for HLA-Cw3-related MHC class I.
T cells and natural killer (NK) cells perform complementary roles in the cellular immune system. T cells identify infected cells directly through recognition of antigenic peptides that are displayed at the target cell surface by the classical major histocompatibility complex (MHC) class I molecules. NK cells monitor the target cell surface for malfunction of this display system, lysing potentially infected cells that might otherwise evade recognition by the T cells. Human killer cell inhibitory receptors (KIRs) control this process by either inhibiting or activating the cytotoxic activity of NK cells via specific binding to MHC class I molecules on the target cell. We report the crystal structure of the extracellular region of the human p58 KIR (KIR2DL3), which is specific for the human MHC class I molecule HLA-Cw3 and related alleles. The structure shows the predicted topology of two tandem immunoglobulin-like domains, but comparison with the previously reported structure of the related receptor KIR2DL1 reveals an unexpected change of 23 degrees in the relative orientation of these domains. The altered orientation of the immunoglobulin-like domains maintains an unusually acute interdomain elbow angle, which therefore appears to be a distinctive feature of the KIRs. The putative MHC class I binding site is located on the outer surface of the elbow, spanning both domains. The unexpected observation that this binding site can be modulated by differences in the relative domain orientations has implications for the general mechanism of KIR-MHC class I complex formation.


Educational attainment and mortality: results from the Sixth Population Census in China.
Health and education are two closely related factors that affect human development. A limited number of studies have been conducted in China, most of which have been based on small sample sizes and with inconsistent results. The study investigates the association between mortality rate and educational level in China based on the sixth national population census in 2010. This is large-scale population study based on the nationally administrated data sets of population census in 2010, 2000 and 1990. The 2010 census covered a total population of 1 332 810,869 in China. In general, standardized mortality rate decreased as educational level increased. The standardized mortality rate is higher among males than among females with equivalent educational levels. The standardized mortality rate in all the educational groups declined to varying degrees from 1990. 2000 to 2010. The standardised mortality rate declined with increasing educational levels from no education to university undergraduate groups in 1990, 2000 and 2010. The standardized mortality rate declined as the degree of education increased in cities, towns, and villages, but gradually increased at the same educational level from cities, towns, to villages in general. The difference in each region is considerable and the population quality of the developed area is generally high. The percentage of the uneducated population to the total population aged 15 years and over (%) was positively correlated with the standardized mortality rate. By contrast, the percentage of the population with a high school education to the total population aged 6 years and over (%) was negatively correlated with the standardized mortality rate. We found that educational level was negatively correlated with the mortality rate. The crude and standardized death rate is lower among individuals with higher educational level. Together with previous research findings, this study indicates that improving total population education attainment remains an important challenge that requires imperative action, while reducing educational inequities remains crucial for the government.


Meteorological factors affecting the risk of transmission of HPAI in Miyazaki, Japan.
Highly pathogenic avian influenza (HPAI) outbreaks engender a severe economic impact on the poultry industry and public health. Migratory waterfowl are considered the natural hosts of HPAI virus, and HPAI viruses are known to be transmitted over long distances during seasonal bird migration. Bird migration is greatly affected by the weather. Many studies have shown the relationship between either autumn or spring bird migration and climate. However, few studies have shown the relationship between annual bird migration and annual weather. This study aimed to establish a model for the number of migratory waterfowl involved in HPAI virus transmission based on meteorological data. From 136 species of waterfowl that were observed at Futatsudate in Miyazaki, Japan, from 2008 to 2016, we selected potential high-risk species that could introduce the HPAI virus into Miyazaki and defined them as 'risky birds'. We also performed cluster analysis to select meteorological factors. We then analysed the meteorological data and the total number of risky birds using a generalised linear mixed model. We selected 10 species as risky birds: Mallard (Anas platyrhynchos), Northern pintail (Anas acuta), Eurasian wigeon (Anas penelope), Eurasian teal (Anas crecca), Common pochard (Aythya ferina), Eurasian coot (Fulica atra), Northern shoveler (Anas clypeata), Common shelduck (Tadorna tadorna), Tufted duck (Aythya fuligula) and Herring gull (Larus argentatus). We succeeded in clustering 35 meteorological factors into four clusters and identified three meteorological factors associated with their migration: (1) the average daily maximum temperature; (2) the mean value of global solar radiation and (3) the maximum daily precipitation. We thus demonstrated the relationship between the number of risky birds and meteorological data. The dynamics of migratory waterfowl was relevant to the risk of an HPAI outbreak, and our data could contribute to cost and time savings in strengthening preventive measures against epidemics.


Clinicians' Guide to Obtaining a Valid Auditory Brainstem Response to Determine Hearing Status: Signal, Noise, and Cross-Checks.
The auditory brainstem response (ABR) is a powerful tool for making clinical decisions about the presence, degree, and type of hearing loss in individuals in whom behavioral hearing thresholds cannot be obtained or are not reliable. Although the test is objective, interpretation of the results is subjective. This review provides information about evidence-based criteria, suggested by the 2013 Newborn Hearing Screening Program guidelines, and the use of cross-check methods for making valid interpretations about hearing status from ABR recordings. The use of an appropriate display scale setting, templates of expected response properties, and objective criteria to estimate the residual noise, signal level, and signal-to-noise ratio will provide quality data for determining ABR thresholds. Cross-checks (e.g., immittance measures, otoacoustic emissions testing, functional indications of a child's hearing) are also needed to accurately interpret the ABR. Using evidence-based ABR signal detection criteria and considering the results within the context of other physiologic tests and assessments of hearing function will improve the clinician's accuracy for detecting hearing loss and, when present, the degree of hearing loss. Diagnostic accuracy will ensure that appropriate remediation is initiated and that children or infants with normal hearing are not subjected to unnecessary intervention.


Evaluation of gastroenterology and hepatology articles on Wikipedia: are they suitable as learning resources for medical students?
With the changes introduced to medical curricula, medical students use learning resources on the Internet such as Wikipedia. However, the credibility of the medical content of Wikipedia has been questioned and there is no evidence to respond to these concerns. The aim of this paper was to critically evaluate the accuracy and reliability of the gastroenterology and hepatology information that medical students retrieve from Wikipedia. The Wikipedia website was searched for articles on gastroenterology and hepatology on 28 May 2013. Copies of these articles were evaluated by three assessors independently using an appraisal form modified from the DISCERN instrument. The articles were scored for accuracy of content, readability, frequency of updating, and quality of references. A total of 39 articles were evaluated. Although the articles appeared to be well cited and reviewed regularly, several problems were identified with regard to depth of discussion of mechanisms and pathogenesis of diseases, as well as poor elaboration on different investigations. Analysis of the content showed a score ranging from 15.6±0.6 to 43.6±3.2 (mean±SD). The total number of references in all articles was 1233, and the number of references varied from 4 to 144 (mean±SD, 31.6±27.3). The number of citations from peer-reviewed journals published in the last 5 years was 242 (28%); however, several problems were identified in the list of references and citations made. The readability of articles was in the range of -8.0±55.7 to 44.4±1.4; for all articles the readability was 26±9.0 (mean±SD). The concordance between the assessors on applying the criteria had mean κ scores in the range of 0.61 to 0.79. Wikipedia is not a reliable source of information for medical students searching for gastroenterology and hepatology articles. Several limitations, deficiencies, and scientific errors have been identified in the articles examined.


Cost-effectiveness analysis of pneumococcal polysaccharide vaccination from age 60 in São Paulo State, Brazil.
Vaccination of adults aged 60 years and older against Streptococcus pneumonia is not recommended in Brazil. The 23-valent polysaccharide pneumococcal vaccine (PPV23) is only available for institutionalized persons or with underlying diseases despite the substantial medical and economic burden related to pneumococcal infections in adults over than 59 years. The study aimed at evaluating the cost effectiveness of implementing a large PPV program in this population. This analysis was performed using a static decision tree model. Demographic and epidemiological data were obtained from Brazilian official sources and international literature. Economic data were obtained from a study performed in 2007 in a public and a private hospital located in Sao Paulo. Vaccination was assumed to protect for 5 years with 60% effectiveness against bacteremic pneumococcal pneumonia (BPP) and 21% effectiveness against non bacteremic pneumococcal pneumonia (NBPP). Deterministic and sensitivity analyses were performed. The pneumococcal polysaccharide vaccination saved 5,218 life year gained (LYG). The vaccination program was found to be cost effective in the social security and public health care perspectives with a mean incremental cost-effectiveness ratio of R$10,887 and R$8,281 per LYG respectively. Results were sensitive to the vaccine effectiveness against NBPP, the incidence and case-fatality rate of NBPP. From a societal perspective, PPV23 program for adults 60 and older was found to be cost-saving. Pneumococcal polysaccharide vaccination is clinically and economically favored over the present vaccination strategy, in which persons aged over 59 years in Sao Paulo, have not been vaccinated.


Classification of Alzheimer's Disease with and without Imagery using Gradient Boosted Machines and ResNet-50.
Alzheimer's is a disease for which there is no cure. Diagnosing Alzheimer's disease (AD) early facilitates family planning and cost control. The purpose of this study is to predict the presence of AD using socio-demographic, clinical, and magnetic resonance imaging (MRI) data. Early detection of AD enables family planning and may reduce costs by delaying long-term care. Accurate, non-imagery methods also reduce patient costs. The Open Access Series of Imaging Studies (OASIS-1) cross-sectional MRI data were analyzed. A gradient boosted machine (GBM) predicted the presence of AD as a function of gender, age, education, socioeconomic status (SES), and a mini-mental state exam (MMSE). A residual network with 50 layers (ResNet-50) predicted the clinical dementia rating (CDR) presence and severity from MRI's (multi-class classification). The GBM achieved a mean 91.3% prediction accuracy (10-fold stratified cross validation) for dichotomous CDR using socio-demographic and MMSE variables. MMSE was the most important feature. ResNet-50 using image generation techniques based on an 80% training set resulted in 98.99% three class prediction accuracy on 4139 images (20% validation set) at Epoch 133 and nearly perfect multi-class predication accuracy on the training set (99.34%). Machine learning methods classify AD with high accuracy. GBM models may help provide initial detection based on non-imagery analysis, while ResNet-50 network models might help identify AD patients automatically prior to provider review.


Enhanced emotional responses during social coordination with a virtual partner.
Emotion and motion, though seldom studied in tandem, are complementary aspects of social experience. This study investigates variations in emotional responses during movement coordination between a human and a Virtual Partner (VP), an agent whose virtual finger movements are driven by the Haken-Kelso-Bunz (HKB) equations of Coordination Dynamics. Twenty-one subjects were instructed to coordinate finger movements with the VP in either inphase or antiphase patterns. By adjusting model parameters, we manipulated the 'intention' of VP as cooperative or competitive with the human's instructed goal. Skin potential responses (SPR) were recorded to quantify the intensity of emotional response. At the end of each trial, subjects rated the VP's intention and whether they thought their partner was another human being or a machine. We found greater emotional responses when subjects reported that their partner was human and when coordination was stable. That emotional responses are strongly influenced by dynamic features of the VP's behavior, has implications for mental health, brain disorders and the design of socially cooperative machines.


Shared and Distinct Neuroanatomic Regions Critical for Tool-related Action Production and Recognition: Evidence from 131 Left-hemisphere Stroke Patients.
The inferior frontal gyrus and inferior parietal lobe have been characterized as human homologues of the monkey "mirror neuron" system, critical for both action production (AP) and action recognition (AR). However, data from brain lesion patients with selective impairment on only one of these tasks provide evidence of neural and cognitive dissociations. We sought to clarify the relationship between AP and AR, and their critical neural substrates, by directly comparing performance of 131 chronic left-hemisphere stroke patients on both tasks--to our knowledge, the largest lesion-based experimental investigation of action cognition to date. Using voxel-based lesion-symptom mapping, we found that lesions to primary motor and somatosensory cortices and inferior parietal lobule were associated with disproportionately impaired performance on AP, whereas lesions to lateral temporo-occipital cortex were associated with a relatively rare pattern of disproportionately impaired performance on AR. In contrast, damage to posterior middle temporal gyrus was associated with impairment on both AP and AR. The distinction between lateral temporo-occipital cortex, critical for recognition, and posterior middle temporal gyrus, important for both tasks, suggests a rough gradient from modality-specific to abstract representations in posterior temporal cortex, the first lesion-based evidence for this phenomenon. Overall, the results of this large patient study help to bring closure to a long-standing debate by showing that tool-related AP and AR critically depend on both common and distinct left hemisphere neural substrates, most of which are external to putative human mirror regions.


Use of the 'Precessions' process for prepolishing and correcting 2D & 2(1/2)D form.
The Precessions process polishes complex surfaces from the ground state preserving the ground-in form, and subsequently rectifies measured form errors. Our first paper introduced the technology and focused on the novel tooling. In this paper we describe the unique CNC machine tools and how they operate in polishing and correcting form. Experimental results demonstrate both the '2D' and '2(1/2)D' form-correction modes, as applied to aspheres with rotationally-symmetric target-form.


Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy.
The development of a malignant tumor involves the progressive acquisition of mutations and epigenetic abnormalities in multiple genes that have highly diverse functions. Some of these genes code for pathways of signal transduction that mediate the action of growth factors. The enzyme protein kinase C plays an important role in these events and in the process of tumor promotion. Therefore, we examined the effects of three inhibitors of protein kinase C, CGP 41251, RO 31-8220, and calphostin C, on human glioblastoma cells. These compounds inhibited growth and induced apoptosis; these activities were associated with a decrease in the level of CDC2 and cyclin B1/CDC2-associated kinase activity. This may explain why the treated cells accumulated in G2-M. In a separate series of studies, we examined abnormalities in cell cycle control genes in human cancer. We have found that cyclin D1 is frequently overexpressed in a variety of human cancers. Mechanistic studies indicate that cyclin D1 can play a critical role in carcinogenesis because: overexpression enhances cell transformation and tumorigenesis; introduction of an antisense cyclin D1 cDNA into either human esophageal or colon cancer cells reverts their malignant phenotype; and overexpression of cyclin D1 can enhance the amplification of other genes. The latter finding suggests that cyclin D1 can enhance genomic instability and, thereby, the process of tumor progression. Therefore, inhibitors of the function of cyclin D1 may be useful in both cancer chemoprevention and therapy. We obtained evidence for the existence of homeostatic feedback loops between cyclins D1 or E and the cell cycle inhibitory protein p27Kip1. On the basis of these and other findings, we hypothesize that, because of their disordered circuitry, cancer cells suffer from "gene addiction" and "gene hypersensitivity," disorders that might be exploited in both cancer prevention and therapy.


Protective effects of gelam honey against oxidative damage in young and aged rats.
Aging is characterized by progressive decline in physiological and body function due to increase in oxidative damage. Gelam honey has been accounted to have high phenolic and nonphenolic content to attenuate oxidative damage. This study was to determine the effect of local gelam honey on oxidative damage of aged rats. Twenty-four male Spraque-Dawley rats were divided into young (2 months) and aged (19 months) groups. Each group was further divided into control (fed with plain water) and supplemented with 2.5 mg/kg body weight of gelam honey for 8 months. DNA damage level was determined by comet assay and plasma malondialdehyde (MDA) by high performance liquid chromatography (HPLC). The activity of blood and cardiac antioxidant enzymes was determined by spectrophotometer. The DNA damage and MDA level were reduced in both gelam honey supplemented groups. Gelam honey increases erythrocytes CAT and cardiac SOD activities in young and cardiac CAT activity in young and aged groups. The DNA damage was increased in the aged group compared to young group, but reduced at the end of the study. The decline of oxidative damage in rats supplemented with gelam honey might be through the modulation of antioxidant enzyme activities.


A 24-week, multicenter, open-label, randomized study to compare changes in glucose metabolism in patients with schizophrenia receiving treatment with olanzapine, quetiapine, or risperidone.
This randomized, 24-week, flexible-dose study compared changes in glucose metabolism in patients with DSM-IV schizophrenia receiving initial exposure to olanzapine, quetiapine, or risperidone. The hypothesized primary endpoint was change (baseline to week 24) in area under the curve (AUC) 0- to 2-hour plasma glucose values during an oral glucose tolerance test (OGTT); primary analysis: olanzapine versus quetiapine. Secondary endpoints included mean change in AUC 0- to 2-hour plasma insulin values, insulin sensitivity index, and fasting lipids. The first patient enrolled on April 29, 2004, and the last patient completed the study on October 24, 2005. Mean weight change (kg) over 24 weeks was +3.7 (quetiapine), +4.6 (olanzapine), and +3.6 (risperidone). Based on data from 395 patients (quetiapine, N = 115 [mean dose = 607.0 mg/day], olanzapine, N = 146 [mean dose = 15.2 mg/day], and risperidone, N = 134 [mean dose = 5.2 mg/day]), mean change in AUC 0- to 2-hour glucose value (mg/dL x h) at week 24 was significantly lower for quetiapine versus olanzapine (t = 1.98, df = 377, p = .048). Increases in AUC 0- to 2-hour glucose values were statistically significant with olanzapine (+21.9 mg/dL x h, 95% CI = 11.5 to 32.4 mg/dL x h) and risperidone (+18.8 mg/dL x h, 95% CI = 8.1 to 29.4 mg/dL x h), but not quetiapine (+9.1 mg/dL x h, 95% CI = -2.3 to 20.5 mg/dL x h). AUC 0- to 2-hour insulin values increased statistically significantly with olanzapine (+24.5%, 95% CI = 11.5% to 39.0%), but not with quetiapine or risperidone. Reductions in insulin sensitivity index were statistically significant with olanzapine (-19.1%, 95% CI = -27.9% to -9.3%) and risperidone (-15.8%, 95% CI = -25.1% to -5.4%), but not quetiapine. Total cholesterol and low-density lipoprotein levels increased statistically significantly with olanzapine (+21.1 mg/dL, 95% CI = 13.0 to 29.2 mg/dL, and +20.5 mg/dL, 95% CI = 13.8 to 27.1 mg/dL, respectively) and quetiapine (+13.1 mg/dL, 95% CI = 4.3 to 21.9 mg/dL, and +13.3 mg/dL, 95% CI = 6.1 to 20.5 mg/dL, respectively), but not risperidone. Statistically significant increases in triglycerides (+30.9 mg/dL, 95% CI = 10.9 to 51.0 mg/dL), total cholesterol/high-density lipoprotein (HDL) ratio (0.5, 95% CI = 0.2 to 0.8), and triglyceride/HDL ratio (0.3, 95% CI = 0.0 to 0.6) were observed with olanzapine only. The results indicate a significant difference in the change in glucose tolerance during 6 months' treatment with olanzapine versus quetiapine, with significant reductions on olanzapine and risperidone, but not quetiapine; these differential changes were largely explained by changes in insulin sensitivity. clinicaltrials.gov Identifier: NCT00214578.


Grandiose narcissism influences the phenomenology of remembered past and imagined future events.
Little empirical work has examined future thinking in narcissistic grandiosity. We here extend prior work finding that people scoring high in grandiosity have self-bolstering tendencies in remembering past events, and we consider whether these tendencies extend to imagining future events. Across an initial study (N = 112) and replication (N = 169), participants wrote about remembered past events and imagined future events in which they embodied or would embody either positive or negative traits. Participants then rated those events on several subjective measures. We find that people scoring higher in grandiosity remember past events in which they embody positive traits with greater detail and ease than past events in which they embody negative traits. These same effects persist when people scoring high in grandiosity imagine possible events in their future. Those scoring higher in grandiosity endorse thinking about positive events in their past and future more frequently than negative events, and they judge positive future events as more plausible than negative future events. These tendencies did not extend to objective detail provided in their written narratives about these events. Taken together, these findings demonstrate that grandiosity is associated with self-bolstering tendencies in both remembering the past and imagining the future.


Kawasaki Disease Following the 13-valent Pneumococcal Conjugate Vaccine and Rotavirus Vaccines.
Temporal associations between Kawasaki disease (KD) and childhood vaccines have been reported. Limited data on KD following 13-valent pneumococcal conjugate (PCV13) and rotavirus vaccines are available. We conducted a self-controlled risk interval study using Vaccine Safety Datalink electronic health record data to investigate the risk of KD following PCV13 and rotavirus vaccines in children <2 years of age who were born from 2006 to 2017. All hospitalized KD cases identified by International Classification of Diseases diagnosis codes that fell within predefined risk (days 1-28 postvaccination) and control (days 29-56 for doses 1 and 2, and days 43-70 for doses 3 and 4) intervals were confirmed by manual chart review. During the study period, 655 cases of KD were identified by International Classification of Diseases codes. Of these, 97 chart-confirmed cases were within risk or control intervals. In analyses, the age-adjusted relative risk for KD following any dose of PCV13 was 0.75 (95% confidence interval, 0.47-1.21). Similarly, the age-adjusted relative risk for KD following any dose of rotavirus vaccine was 0.66 (95% CI, 0.40-1.09). Overall, there was no evidence of an elevated risk of KD following PCV13 or rotavirus vaccines by dose. In addition, no statistically significant temporal clustering of KD cases was identified during days 1 to 70 postvaccination. PCV13 and rotavirus vaccination were not associated with an increased risk of KD in children <2 years of age. Our findings provide additional evidence for the overall safety of PCV13 and rotavirus vaccines.


Development and validation of a brief screening version of the Childhood Trauma Questionnaire.
The goal of this study was to develop and validate a short form of the Childhood Trauma Questionnaire (the CTQ-SF) as a screening measure for maltreatment histories in both clinical and nonreferred groups. Exploratory and confirmatory factor analyses of the 70 original CTQ items were used to create a 28-item version of the scale (25 clinical items and three validity items) and test the measurement invariance of the 25 clinical items across four samples: 378 adult substance abusing patients from New York City, 396 adolescent psychiatric inpatients, 625 substance abusing individuals from southwest Texas, and 579 individuals from a normative community sample (combined N=1978). Results showed that the CTQ-SF's items held essentially the same meaning across all four samples (i.e., measurement invariance). Moreover, the scale demonstrated good criterion-related validity in a subsample of adolescents on whom corroborative data were available. These findings support the viability of the CTQ-SF across diverse clinical and nonreferred populations.


Socioeconomic impact of road traffic injuries in West Africa: exploratory data from Nigeria.
Road traffic injuries (RTIs) are increasingly contributing to the burden of disease in sub-Saharan Africa, yet little is known about the economic consequences and disability associated with them. To explore cost and disability consequences of RTIs in Nigeria. A population-based survey using two-stage stratified cluster sampling. SUBJECT/SETTING: Information on care-seeking choice, cost of treatment, ability to work, reduction in earnings, and disability were collected on 127 subjects who had suffered an RTI, of 3082 study subjects in seven Nigerian states. Univariate analysis was used to estimate frequency of disability, types of care sought, and trends for work lost, functional ability and cost of treatment. Unadjusted bivariate analysis was performed to explore care-seeking, cost of care, and work lost among disabled and non-disabled people. RTIs resulted in disability for 29.1% of subjects, while 13.5% were unable to return to work. Of the disabled people, 67.6% were unable to perform activities of daily living, 16.7% consequently lost their jobs, and 88.6% had a reduction in earnings. Private physician and hospital treatment were the most common forms of initial treatment sought, but traditional treatment was the most common second form of care sought. Average direct costs of informal and formal treatment were US$6.65 and US$35.64, respectively. Disabled people were more likely to seek formal care (p=0.003) and be unable to work (p=0.002). Economic and functional ramifications must be included in the spectrum of consequences of RTIs to fully appreciate the extent of the burden of disease, implying that health systems should not only address the clinical consequences of RTIs, but the financial ones as well.


Characterization of distinct tethering and intracellular targeting domains in AKAP75, a protein that links cAMP-dependent protein kinase II beta to the cytoskeleton.
Cyclic AMP-dependent protein kinase II beta (PKAII beta) is the principal mediator of cAMP action in neurons. A Kinase Anchor Proteins (AKAPs) are enriched in forebrain neurons and have distinct high affinity binding domains for the regulatory subunit (RII beta) of PKAII beta and components of the dendritic cytoskeleton. The selective accumulation of AKAP.RII beta complexes near dendritic microtubules tethers PKAII beta in proximity with adenylate cyclase in the synaptic plasma membrane and cytoskeletal proteins that are substrates for the kinase, thereby creating intraneuronal target sites for signals carried by cAMP. We have characterized the targeting (anchoring) and tethering (RII beta binding) domains of a prototypic anchor protein AKAP75. Deletion of N-terminal residues 27-48 generated a truncated RII beta-binding protein that partitions equally between the cytosol and detergent-insoluble fractions of HEK293 cells. Further removal of a non-adjacent sequence (residues 77-91) produced a cytosolic protein with unimpaired RII beta binding activity. Thus, two noncontiguous domains mediate the intracellular localization of AKAP75. Boundaries for the RII beta tethering domain were mapped to residues 392-413 by scanning mutagenesis. Residues containing long aliphatic side chains are essential for the high affinity binding of RII beta by AKAP75. Contributions of hydrophobic amino acids to tethering activity also depend on the position of the residue in the sequence. Certain conservative mutations that should not alter significantly the overall hydrophobicity or helicity of the tethering region (e.g. replacement of Leu with Ala) diminish the RII beta binding activity of AKAP75.


NTP Toxicology and Carcinogenesis Studies of 1,2-Dichloropropane (Propylene Dichloride) (CAS No. 78-87-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
1,2-Dichloropropane is a chemical intermediate widely used in the production of tetrachloroethylene and carbon tetrachloride. It is an oil and fat solvent in certain furniture finishes, dry cleaning fluids, and paint removers and has been used to fumigate grain and soil and to control peach tree borers. Approximately 77 million pounds of 1,2-dichloropropane were produced in the United States in 1980. The current 8-hour time-weighted-average concentration to which workers may be exposed to is 75 ppm. Carcinogenesis studies of 1,2-dichloropropane (<99% pure) were conducted by administering the chemical in corn oil by gavage to groups of 50 female F344/N rats and 50 male and 50 female B6C3F1 mice at doses of 125 or 250 mg/kg body weight and to groups of 50 male F344/N rats at doses of 62 or 125 mg/kg body weight. Doses were administered five times per week for 103 weeks. Vehicle control groups of 50 rats and 50 mice of each sex received an equivalent amount of corn oil by gavage on the same dosing schedule. Survival was reduced for high dose female rats (P<0.001) and for high dose female mice (P<0.05) relative to controls; 16/50 high dose female rats and 26/50 high dose female mice survived to the end of the experiment. Survival in the other groups was comparable to the control groups. In female mice, ovarian, uterine, or multiple organ infections may have contributed to the deaths of 5/11 vehicle control, 9/14 low dose, and 14/22 high dose animals that died before the end of the study. There was no evidence of an adverse effect on survival in male rats or in male mice. Mean body weights of high dose male (-14%) and high dose female (-24%) rats were lower than those of the controls. Low dose rats and all groups of mice had mean body weights comparable to the controls. High dose female rats had increased incidences of both clear-cell changes and necrosis of the liver; but there was no increase in the incidence of liver tumors in the female rats. There was no treatment-related effects observed in the male rats, other than decreased body weights. Dose-related increases were observed for adenomas of the liver in both male (control, 7/50; low dose, 10/50; high dose 17/50) and female (1/50, 5/50, 5/50) mice. The increase in the frequency of liver carcinomas supported the evidence that there was a neoplastic response in the mouse liver for both sexes (males: 11/50, 17/50, 16/50, females: 1/50, 3/50, 4/50). Hepatocytomegaly and hepatic necrosis were increased in male mice, but not in female mice. A dose related increase in adenocarcinomas of the mammary gland was observed in female rats (control, 1/50; low dose, 2/50; high dose, 5/50) with the majority of these tumors being found at the end of the study (1/37, 3%; 2/43, 5%; 4/16, 25%). The incidence of mammary adenocarcinomas was increased when compared to the historical controls for this laboratory (3/150, 2.0%) and for all laboratories combined (11/895, 1.2%). Mammary fibroadenomas were decreased in the high dose treated female rats (15/50, 20/50, 7/50). The mutagenic activity of 1,2-dichloropropane was marginal. The compound was tested in strains TA100, TA98, TA1537, and TA1535 of Salmonella typhimurium in the presence or absence of S9 and no clearly positive response was obtained. Chromosomal aberration and sister chromatid exchange data showed that 1,2-dichloropropane caused increases in both in the absence or presence of S9. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity for male F344/N rats receiving 62 or 125 mg/kg. For female rats there was equivocal evidence of carcinogenicity in that 250 mg/kg 1,2-dichloropropane caused a marginally increased incidence of adenocarcinomas in the mammary gland; these borderline malignant lesions occurred concurrent with decreased survival and reduced body weight gain. There was some evidence of carcinogenicity for male and female B6C3F1 mice exposed to 1,2-dichloropropane, as indicated by increased incidences of hepatocellular neoplasms, primarily adenomas. Synonym: propylene dichloride


Pharmacokinetics and transcriptional effects of the anti-salmon lice drug emamectin benzoate in Atlantic salmon (Salmo salar L.).
Emamectin benzoate (EB) is a dominating pharmaceutical drug used for the treatment and control of infections by sea lice (Lepeophtheirus salmonis) on Atlantic salmon (Salmo salar L). Fish with an initial mean weight of 132 g were experimentally medicated by a standard seven-day EB treatment, and the concentrations of drug in liver, muscle and skin were examined. To investigate how EB affects Atlantic salmon transcription in liver, tissues were assessed by microarray and qPCR at 7, 14 and 35 days after the initiation of medication. The pharmacokinetic examination revealed highest EB concentrations in all three tissues at day 14, seven days after the end of the medication period. Only modest effects were seen on the transcriptional levels in liver, with small fold-change alterations in transcription throughout the experimental period. Gene set enrichment analysis (GSEA) indicated that EB treatment induced oxidative stress at day 7 and inflammation at day 14. The qPCR examinations showed that medication by EB significantly increased the transcription of both HSP70 and glutathione-S-transferase (GST) in liver during a period of 35 days, compared to un-treated fish, possibly via activation of enzymes involved in phase II conjugation of metabolism in the liver. This study has shown that a standard seven-day EB treatment has only a modest effect on the transcription of genes in liver of Atlantic salmon. Based on GSEA, the medication seems to have produced a temporary oxidative stress response that might have affected protein stability and folding, followed by a secondary inflammatory response.


Dietary fructooligosaccharides prevent osteopenia after gastrectomy in rats.
Postgastrectomy osteopenia is observed generally in humans. Fructooligosaccharides increase the absorption of calcium from the large intestine of healthy rats. Thus, we have examined whether they stimulate calcium absorption and prevent osteopenia in rats following total gastrectomy. Rats were subjected to either a sham surgical operation or Billoth II gastrectomy. Seven rats from each surgical treatment group were fed a control diet, and another seven rats of each treatment group were fed a diet containing fructooligosaccharides (75 g/kg diet) for 4 wk. For 5 d each week, feces were collected, and the calcium and phosphorus contents were measured for calculation of the absorption of these minerals. At the end of the experiment, the rats were killed and bones were collected. The net calcium absorption, calcium content and bone mineral density of the femur and tibia in gastrectomized rats fed the control diet were significantly less than those in sham-operated rats fed control diet. The net calcium absorption in rats fed the fructooligosaccharides diet was greater than that in rats fed control diet. Moreover, dietary fructooligosaccharides prevented the decrease in the calcium content and bone mineral density in gastrectomized rats. Dietary fructooligosaccharides enhanced calcium absorption and prevented the changes indicative of postgastrectomy osteopenia such as decreases in bone calcium content and bone mineral density in gastrectomized rats.


OPD measurement and dispersion reduction in a monolithic interferometer.
We describe a white light fringe scanning and pupil bisecting method of measuring the optical path difference (OPD) between arms of a monolithic nulling interferometer that is designed to enable direct imaging of planetary companions and the environments around nearby stars. This measurement is used to determine the differential thicknesses of optically contacted compensator plates used to reduce OPD, which can drastically impair the optic's performance in broadband light. By making this correction, we were able to reduce the initial OPD from 949+/-44 nm to 63+/-10 nm. In the absence of any other asymmetries that can compromise the null, such a correction corresponds to an increase in an R-band (lambda(c) = 648 nm) nulling bandpass from monochromatic to 25%.


More is better: combination therapies for myelodysplastic syndromes.
The myelodysplastic syndromes (MDS) are a heterogenous collection of clonal hematopoietic malignancies that exist as a subgroup of the myeloid neoplasms as classified by the World Health Organization (WHO). They are characterized by ineffective hematopoiesis, subsequent cytopenias, transformation to acute myeloid leukemia (AML), and poor overall survival. There are currently three FDA-approved medications for MDS; lenalidomide, azacitidine, and decitabine. The role of these agents is to diminish the clinical impact of MDS and delay its progression to AML. However, despite known results with these monotherapies, recent clinical trials with a variety of combinations for MDS have demonstrated promising results. These trials include combinations of hypomethylating agents, histone deacetylase inhibitors, growth factors, and chemotherapy among others. In this paper we review the current literature on combination therapies in MDS, analyze on-going and concluded trials, and suggest future possibilities for combination strategies in MDS.


Pectin from Passiflora edulis shows anti-inflammatory action as well as hypoglycemic and hypotriglyceridemic properties in diabetic rats.
Flour made from Passiflora edulis fruit peel has been used in Brazil to treat diabetes. This study evaluated the effects of pectin from P. edulis on rats with alloxan-induced diabetes, on myeloperoxidase release from human neutrophils, and on carrageenan-induced paw edema. In the experiments on carrageenan-induced paw edema, paws were dissected for hematoxylin-eosin staining and immunohistochemistry determinations of tumor necrosis factor-α and inducible nitric oxide synthase. Male Wistar rats were divided into the following groups: diabetic controls and diabetic treated with pectin daily for 5 days (0.5-25 mg/kg orally). Glibenclamide and metformin were used as reference drugs. Forty-eight hours after alloxan administration, blood measures were determined (before treatment) and again 5 days later (after treatment). Pectin decreased blood glucose and triglyceride levels in diabetic rats. Pectin also decreased edema volume and release of myeloperoxidase (0.1-100 μg/mL). It also significantly decreased neutrophil infiltration and partially decreased immunostaining for tumor necrosis factor-α and inducible nitric oxide synthase. In conclusion, these data indicated that pectin, a bioactive compound present in P. edulis, has potential as a useful alternative treatment for type 2 diabetes. Its anti-inflammatory properties are probably involved in its antidiabetic action.


A prospective exploration of farm, farmer, and animal characteristics in human-animal relationships: An epidemiological survey.
Human-animal relationships are essential for dairy farming. They affect work comfort and efficiency, as well as milk production. A poor human-animal relationship can result in stress and accidents to both animals and caretakers and needs to be improved. However, many studies have demonstrated the multifactoriality of these relationships. We aimed at assessing the relative importance of the various factors expected to be associated with poor human-animal relationships. On 118 dairy farms, we applied a standardized avoidance distance test to cows at the feeding rack. The sample of farms covered a wide range of situations: lowland versus highland, small versus medium size farms, cubicles versus deep-bedded systems, milking parlor versus automatic milking systems, and Holstein versus Montbéliarde breeds. We used Poisson regression to analyze the links between the number of cows that accepted being touched, and farm characteristics, animals, management, and farmers' attitudes. A multivariate analysis yielded a final model that explained 32.7% of the variability between farms. Calving conditions ("Main calving location" and "Cleaning or adding litter after calving") accounted for a significant part of the variability observed (respectively 25.8 and 13.6% of variability explained by the model, SSB). Fewer cows accepted being touched on farms where the main calving location was in the barn, and where farmers cleaned or added litter after calving. The proportion of cows that accepted being touched increased with the proportion of lean cows in the herd (18.8%), with worker/cow ratio on the farm (11.7%), when farmers considered "health" or "human-cow relationships" as most important issues for farm success (10.4%), and with farmers' years of experience (10.8%). Farmers with more negative behavioral attitudes toward cows had a lower proportion of cows that accepted being touched (8.9%). In conclusion, the human-animal relationship was not found to be associated with farm characteristics (e.g., housing or milking system) but varied with farmers' attitudes and management. We confirm that cows' fear of people is linked to negative attitudes displayed by caretakers toward cows, and is reduced in farms where several caretakers are present. Our study also suggests further exploring the key role of factors linked to calving conditions, as cows are more likely to be afraid of people when disturbed at calving.


Severe Hypertriglyceridemia With New-Onset Type 1 Diabetes in Diabetic Ketoacidosis.
Hypertriglyceridemia is a complication in the presentation of diabetic ketoacidosis (DKA) but has been reported in the pediatric population infrequently. We report a 13-year-old female with new onset type 1 diabetes in DKA, who developed extreme hypertriglyceridemia. Our patient's case is unique as her triglyceride levels were markedly higher than those in other reports and required a longer duration of time to resolve. We review the literature on the concomitant presentation of DKA and hypertriglyceridemia, as well as its pathophysiology and treatment.


Searching standard parameters for volumetric modulated arc therapy (VMAT) of prostate cancer.
Since December 2009 a new VMAT planning system tool is available in Oncentra MasterPlan v3.3 (Nucletron B.V.). The purpose of this study was to work out standard parameters for the optimization of prostate cancer. For ten patients with localized prostate cancer plans for simultaneous integrated boost were optimized, varying systematically the number of arcs, collimator angle, the maximum delivery time, and the gantry spacing. Homogeneity in clinical target volume, minimum dose in planning target volume, median dose in the organs at risk, maximum dose in the posterior part of the rectum, and number of monitor units were evaluated using student's test for statistical analysis. Measurements were performed with a 2D-array, taking the delivery time, and compared to the calculation by the gamma method. Plans with collimator 45° were superior to plans with collimator 0°. Single arc resulted in higher minimum dose in the planning target volume, but also higher dose values to the organs at risk, requiring less monitor units per fraction dose than dual arc. Single arc needs a higher value (per arc) for the maximum delivery time parameter than dual arc, but as only one arc is needed, the measured delivery time was shorter and stayed below 2.5 min versus 3 to 5 min. Balancing plan quality, dosimetric results and calculation time, a gantry spacing of 4° led to optimal results. A set of parameters has been found which can be used as standard for volumetric modulated arc therapy planning of prostate cancer.


Protein interactions and consensus clustering analysis uncover insights into herpesvirus virion structure and function relationships.
Infections with human herpesviruses are ubiquitous and a public health concern worldwide. Current treatments reduce the severity of some symptoms associated to herpetic infections but neither remove the viral reservoir from the infected host nor protect from the recurrent symptom outbreaks that characterise herpetic infections. The difficulty in therapeutically tackling these viral systems stems in part from their remarkably large proteomes and the complex networks of physical and functional associations that they tailor. This study presents our efforts to unravel the complexity of the interactome of herpes simplex virus type 1 (HSV1), the prototypical herpesvirus species. Inspired by our previous work, we present an improved and more integrative computational pipeline for the protein-protein interaction (PPI) network reconstruction in HSV1, together with a newly developed consensus clustering framework, which allowed us to extend the analysis beyond binary physical interactions and revealed a system-level layout of higher-order functional associations in the virion proteome. Additionally, the analysis provided new functional annotation for the currently undercharacterised protein pUS10. In-depth bioinformatics sequence analysis unravelled structural features in pUS10 reminiscent of those observed in some capsid-associated proteins in tailed bacteriophages, with which herpesviruses are believed to share a common ancestry. Using immunoaffinity purification (IP)-mass spectrometry (MS), we obtained additional support for our bioinformatically predicted interaction between pUS10 and the inner tegument protein pUL37, which binds cytosolic capsids, contributing to initial tegumentation and eventually virion maturation. In summary, this study unveils new, to our knowledge, insights at both the system and molecular levels that can help us better understand the complexity behind herpesvirus infections.


Development and application of bovine and porcine oligonucleotide arrays with protein-based annotation.
The design of oligonucleotide sequences for the detection of gene expression in species with disparate volumes of genome and EST sequence information has been broadly studied. However, a congruous strategy has yet to emerge to allow the design of sensitive and specific gene expression detection probes. This study explores the use of a phylogenomic approach to align transcribed sequences to vertebrate protein sequences for the detection of gene families to design genomewide 70-mer oligonucleotide probe sequences for bovine and porcine. The bovine array contains 23,580 probes that target the transcripts of 16,341 genes, about 72% of the total number of bovine genes. The porcine array contains 19,980 probes targeting 15,204 genes, about 76% of the genes in the Ensembl annotation of the pig genome. An initial experiment using the bovine array demonstrates the specificity and sensitivity of the array.


Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial.
In North America, no effective therapy has been available for patients with progressive metastatic colorectal cancer after front-line treatment with irinotecan, bolus fluorouracil (FU), and leucovorin (IFL). Patients with metastatic colorectal cancer who progressed after IFL therapy were randomly assigned to bolus and infusional FU and leucovorin (LV5FU2), single-agent oxaliplatin, or the combination (FOLFOX4). This planned interim analysis evaluated objective response rate (RR), time to tumor progression (TTP), and alleviation of tumor-related symptoms (TRS) in an initial cohort of patients. Between November 2000 and September 2001, 463 patients from 120 sites in North America were randomly assigned to treatment. FOLFOX4 proved superior to LV5FU2 in all measures of clinical efficacy. Objective RRs determined by an independent radiology panel were 9.9% for FOLFOX4 versus 0% for LV5FU2 (Fisher's exact test, P <.0001). Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 (two-sided, stratified log-rank test, P <.0001). Relief of TRS occurred in 33% of patients treated with FOLFOX4 versus 12% of patients treated with LVFU2 (chi2 test, P <.001). Single-agent oxaliplatin was not superior to LV5FU2 in any measure of efficacy. Patients treated with FOLFOX4 experienced a higher incidence of clinically significant toxicities than patients treated with LV5FU2, but these toxicities were predictable and did not result in a higher rate of treatment discontinuation or 60-day mortality rate. For patients with metastatic colorectal cancer, second-line treatment with FOLFOX4 is superior to treatment with LVFU2 in terms of RR, TTP, and relief of TRS.